In North America, lung carcinoma and melanoma were considered to be the second and sixth common cancer in 2002, and neuroblastoma is the most common extracranial solid tumor of childhood. Currently, all stage survival rate is 15% in lung carcinoma, 89% in melanoma patients and 80% in neuroblastoma patients in North America. Current therapy approaches include radiation and chemotherapy. However, the poor survival rates underscore the need for developing new approaches. Also, a new cancer therapy is needed to prevent the relapse of tumors after conventional treatments, and improve the low survival rate of lung carcinoma patients, late stage melanoma patients (12% at the stage IV), and late stage neuroblastoma patients.
A lack of effective radiation therapy and chemotherapy of metastatic melanoma (Philip, et al. 2000) has led to interest in developing immunotherapy of melanoma. For developing tumor vaccines of melanoma, two major approaches have been used: 1) immunizations with whole tumor cell extracts or irradiated tumor cells (Takashi, et al. 1999; Hsuch, 2001); 2) immunizations with melanoma associated antigens such as MART-1 or gp100 (Chianese-Bullock, et al. 2002).
Useful targets for developing immunological approaches include gangliosides. One such ganglioside is GD2. The GD2 ganglioside is a self-glycol-lipid antigen. It is usually low or non-immunogenic in humans. This antigen is overexpressed in human melanoma and neuroblastoma lesions, and has a restricted distribution in normal tissues. Previous clinical trials have suggested that GD2 ganglioside appears to be poorly immunogenic in humans. In some clinical trials, a kind of antigen mimics, anti-idiotypic antibody, has been shown to be able to induce anti-GD2 ganglioside immune responses in neuroblastoma patients. Furthermore, GD2/GD3 peptide mimics have been isolated with anti-GD2/GD3 antibody ME36,1 (Qiu et al., 1999).
Anti-GD2 ganglioside monoclonal antibodies have been utilized in immunotherapy of melanoma. In human clinical trials, anti-GD2 ganglioside monoclonal antibodies have been shown to be effective in either melanoma or neuroblastoma patients (Saleh, et al. 1992; Murray, et al. 1994; Yu, et al. 1998; Cheung, et al. 2000; Kushner, et al. 2001). However, these clinical trials also suggest that the dose-dependent side effects can limit the usage of anti-GD2 antibodies (Saleh, et al. 1992). These side effects include severe generalized pain, hyponatremia, fever, rash, paresthesias, weakness, and chronic refractory postural hypotension (Murray, et al. 1994; Slart, et al. 1997; Yu, et al. 1998; Sorkin, et al. 2002). Furthermore, the recurrence of neuroblastoma in patients after treatment with anti-GD2 ganglioside antibodies is common (62 out of 95 patients) (Kramer, et al. 2001). These clinical findings suggest that a low dose, as well as long duration anti-GD2 ganglioside therapy might present an approach to overcome both the severe treatment side effects and potential post-treatment relapse.
Active specific immunotherapy can induce a low dose and long lasting immune response, which may overcome the disadvantages of anti-GD2 ganglioside antibody therapy for melanoma patients. However, GD2 ganglioside is weakly immunogenic, and the antibody responses to GD2 ganglioside are often of the IgM isotype in humans (Tai, et al. 1985). These are most likely due to the lack of a T helper response and/or tolerance to GD2 ganglioside because it is both a self-antigen and a glycolipid antigen. In order to increase the immunogenicity of GD2 ganglioside, GD2 ganglioside has been conjugated with keyhole limpet hemocyanin (KLH). 45% of patients immunized with the conjugate and QS-21 adjuvant developed either anti-GD2 ganglioside IgM or IgG antibody responses with only grade II toxicity. These include local toxicity at the vaccine sites, fatigue, flu-like symptoms, fever, or headache (Chapman, et al. 2000). However, 55% of immunized patients still did not respond to the GD2-KLH conjugates.
Accordingly, there is an ongoing need to develop new immunotherapeutic approaches to cancers such as melanoma, neuroblastoma lung carcinoma.